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Whether Nef-mediated down-modulation of TCR-CD3 protects lentivirus-infected hosts against damaging high levels of immune activation, is under debate. Since HIV-2 Nef ability to down-modulate the TCR-CD3 greatly varied, some of them were highly efficient while others were impaired and have HIV-1 Nef like phenotype for the function. This wide spectrum of the down-modulation function among the HIV-2 Nefs allowed us to analyze the significance of TCR- CD3 down-modulation and its role in activation of CD4+ T cells. The outline suggests that Nef-mediated down-modulation of TCR-CD3 and CD28 plays role in protection of viremic HIV-2-infected individuals against loss of CD4+ T cells. These two basic functions play role in activation of the cells and seemingly delay the activation induced exhaustion and apoptotic death of virally infected CD4+ T cells. However, in accordance, the significant correlation of the level of Nef-mediated down-modulation of TCR-CD3 and the levels of immune activation in HIV-2-infected individuals with comparably low viral loads have been reported (20). Another remarkable discovery is the identification of naturally occurring HIV-2 nef alleles that are selectively impaired in specific functions like surface modulation of CD4, CD28, CD74, MHC-I and more importantly down-modulation of TCR-CD3. These selectively defective Nefs open up ways to study the role of CD4 down-modulation, T cell activation or antigen presentation in viral immune evasion, and effect of these specific functions in pathogenicity in animal models. These selectively defective Nefs in specific functions can play significant role to study the detailed mechanisms involved in AIDS progression in vivo.